CN111187223B - Synthetic method of linagliptin intermediate 2-chloromethyl-4-methyl quinazoline - Google Patents
Synthetic method of linagliptin intermediate 2-chloromethyl-4-methyl quinazoline Download PDFInfo
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- CN111187223B CN111187223B CN202010157569.4A CN202010157569A CN111187223B CN 111187223 B CN111187223 B CN 111187223B CN 202010157569 A CN202010157569 A CN 202010157569A CN 111187223 B CN111187223 B CN 111187223B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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Abstract
The invention relates to the technical field of drug synthesis, and particularly discloses a synthetic method of a latidine intermediate 2-chloromethyl-4-methyl quinazoline. The synthetic method of the latidine intermediate 2-chloromethyl-4-methyl quinazoline comprises the following steps: the 2-chloromethyl-4-methyl quinazoline is synthesized by taking o-aminoacetophenone and chloroacetonitrile as reaction raw materials, acidic ionic liquid as a catalyst and 1, 4-dioxane as a reaction solvent through a catalytic ring closure reaction under an acidic condition. The method has the advantages of wide raw material source, low cost, high safety, easy control of the reaction process, low requirement on reaction conditions and high yield and purity of reaction products.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthetic method of a linagliptin intermediate 2-chloromethyl-4-methyl quinazoline.
Background
Linagliptin (linagliptin) is a novel hypoglycemic drug developed by the German Bridgy Yiger Han pharmacy, is approved by the US FDA in 2011 to be marketed, has a very significant hypoglycemic effect, and has the advantages of not affecting body weight and not increasing hypoglycemic risk.
2-chloromethyl-4-methyl quinazoline is an important intermediate for synthesizing linagliptin, and at present, the following three synthesis processes are published and reported: 1) the method comprises the following steps of (1) carrying out condensation reaction on o-aminoacetophenone and hydroxylamine hydrochloride serving as initial raw materials to obtain 1- (2-aminophenyl) -1-ketoxime, reacting the 1- (2-aminophenyl) -1-ketoxime with chloroacetyl chloride for cyclization to obtain 2-chloromethyl-4-methyl quinazoline-3-oxide, and finally carrying out reduction by phosphorus trichloride to obtain a final product, namely 2-chloromethyl-4-methyl quinazoline; 2) reacting 5-methyl-1H-benzo [ E ] [1,4] diazepin-2 (3H) -one serving as an initial raw material with phosphorus oxychloride to prepare 2-chloromethyl-4-methyl quinazoline; 3) the 2-chloromethyl-4-methyl quinazoline is synthesized by taking o-aminoacetophenone and chloroacetonitrile as initial raw materials and adopting a method of closing rings under the catalysis of hydrogen chloride. The first two synthesis methods use highly toxic products (phosphorus trichloride and phosphorus oxychloride), do not use safe production, have expensive raw materials and low yield of synthesized products, and the third synthesis method has short synthesis route and higher yield, but needs a large amount of hydrogen chloride gas to participate in the reaction and is not favorable for safe production.
Disclosure of Invention
Aiming at the problems that in the existing synthesis method of linagliptin intermediate 2-chloromethyl-4-methyl quinazoline, the used raw materials are highly toxic and are not beneficial to safe production, and the synthesis raw materials are expensive and the synthesis route is complex, the invention provides the synthesis method of linagliptin intermediate 2-chloromethyl-4-methyl quinazoline.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a synthetic method of a linagliptin intermediate 2-chloromethyl-4-methyl quinazoline is characterized in that o-aminoacetophenone and chloroacetonitrile are used as reaction raw materials, acidic ionic liquid is used as a catalyst, 1, 4-dioxane is used as a reaction solvent, and the 2-chloromethyl-4-methyl quinazoline is synthesized through a catalytic ring closure reaction under an acidic condition. The reaction process is as follows:
compared with the prior art, the synthesis method of the linagliptin intermediate 2-chloromethyl-4-methyl quinazoline provided by the invention has the advantages that o-aminoacetophenone and chloroacetonitrile are used as reaction raw materials in a 1, 4-dioxane solvent, and the 2-chloromethyl-4-methyl quinazoline can be generated through one-step reaction under the catalytic action of acidic ionic liquid, the raw materials are wide in source and low in cost, the whole reaction process does not involve the addition and generation of toxic substances, the safety is high, the reaction process is easy to control, the reaction condition requirement is low, the selectivity of the reaction process can be guaranteed by the selection of the reaction solvent and the catalyst, the reaction efficiency is improved, the yield and the purity of the finally obtained reaction product are higher, and the synthesis cost of the 2-chloromethyl-4-methyl quinazoline is greatly reduced.
Preferably, the mol ratio of o-aminoacetophenone to chloroacetonitrile is 1: 1-1.2.
Preferably, the acidic ionic liquid is one of N-methyl-3-sulfopropyl imidazole chloride salt, N-methyl-3-sulfopropyl imidazole hydrogen sulfate salt and N-methyl-3-sulfopropyl imidazole hexafluorophosphate salt.
The selection of the acidic ionic liquid can further improve the reaction efficiency and increase the product yield.
Preferably, the addition amount of the acidic ionic liquid is 2.5-3.5% of the mass of the o-aminoacetophenone.
Preferably, the addition amount of the 1, 4-dioxane is 40-50% of the mass of the o-amino acetophenone.
Preferably, the temperature of the reaction is 5-10 ℃.
Preferably, the acidic condition is maintained by adding dropwise a solution of an inorganic acid to the reaction system.
Preferably, the inorganic acid solution is 25-35 wt% hydrochloric acid, and the reaction is continued for 15-20h after the hydrochloric acid is dropwise added.
Preferably, the dropping speed of the hydrochloric acid is 0.05-0.1ml/s, and the dropping amount is 60-70% of the total mass of the reaction system.
The hydrochloric acid is dripped into the reaction system at a certain speed, so that the phenomenon that the acidic ionic liquid catalyst loses catalytic activity due to salification in the reaction system can be avoided, the catalytic reaction efficiency is further improved, and the normal operation of the reaction and the purity of the product cannot be influenced by the addition of the hydrochloric acid.
Preferably, the method also comprises crystallization after the reaction is completed, wherein the specific crystallization operation is as follows: adding ammonia water with the temperature of 0-10 ℃ and the concentration of 8-12 wt% into the reaction system, keeping the temperature below 10 ℃, stirring for crystallization, filtering, dissolving the obtained filter cake in dichloromethane, and then recrystallizing.
Preferably, the addition amount of the ammonia water is 1.5 to 2.5 times of the volume of the reaction system.
Preferably, the dichloromethane is used in an amount of 2 to 3ml/g of filter cake.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The synthesis method of the 2-chloromethyl-4-methyl quinazoline comprises the following specific operation methods:
preparation of Ionic liquid catalyst N-methyl-3-sulfopropyliminesAzolecarbonium salt: to a round bottom flask was added 50mL of ethyl acetate and 6.1g of 1, 3-propane sultone. In N2Magnetically stirring at 40 deg.C for 0.5h under protection, slowly adding 4.1g of N-methylimidazole dropwise via a constant pressure dropping funnel, and reacting at 80 deg.C for 3 h. After the reaction is finished, the temperature is reduced to room temperature, the mixture is filtered, a filter cake is washed by ethyl acetate, and the N-methyl-3-sulfopropyl imidazole inner salt (white solid) is obtained after vacuum drying. Adding the prepared inner salt into a round-bottom flask, adding 20ml of distilled water, stirring at room temperature to dissolve, slowly dropwise adding concentrated hydrochloric acid (12mol/L) in an equimolar ratio, and stirring at 70 ℃ to react for 8 hours. After the reaction is finished, water is evaporated under reduced pressure at 70 ℃ (the pressure is-0.09 MPa), and the ionic liquid catalyst N-methyl-3-sulfopropyl imidazole chloride is obtained.
67.6g of o-aminoacetophenone, 39.6g of chloroacetonitrile, 30ml of 1, 4-dioxane and 2g of N-methyl-3-sulfopropyl imidazole chloride salt prepared above are added into a 500ml reaction bottle, stirred and dissolved, the temperature of a reaction system is reduced to 5 ℃, 84g of 25 wt% hydrochloric acid is dropwise added into the reaction system, the dropwise adding speed is 0.05ml/s, the reaction temperature is controlled to be constant in the dropwise adding process, and after the dropwise adding is finished, the reaction is continued for 15 hours at the temperature of 5 ℃ to finish the reaction process.
After the reaction, 200ml of ammonia water (the concentration of ammonia water is 8 wt%) at 0 ℃ is added into the reaction system, the mixture is stirred and crystallized for 30min at 10 ℃, a filter cake is obtained by filtration, the filter cake is washed by water and recrystallized by 200ml of dichloromethane, 84.76g of a product is obtained, the yield is 84.67%, and the HPLC purity is 99.5%.
Wherein the yield is the percentage value of the mass of the 2-chloromethyl-4-methyl quinazoline in the crystallized product in the theoretical yield of the 2-chloromethyl-4-methyl quinazoline.
Example 2
The synthesis method of the 2-chloromethyl-4-methyl quinazoline comprises the following specific operation methods:
preparation of ionic liquid catalyst N-methyl-3-sulfopropylimidazole hydrogen sulfate: to a round bottom flask was added 50mL of ethyl acetate and 6.1g of 1, 3-propane sultone. In N2Magnetically stirring at 40 deg.C for 0.5h under protection, slowly adding 4.1g of N-methylimidazole dropwise via a constant pressure dropping funnel, and reacting at 80 deg.C for 3 h. Cooling to room temperature after the reaction is finished, filtering, and using acetic acid for filter cakesWashing with ethyl ester, and vacuum drying to obtain N-methyl-3-sulfopropyl imidazole inner salt (white solid). Adding the prepared inner salt into a round-bottom flask, adding 20ml of distilled water, stirring at room temperature to dissolve, then slowly dropwise adding concentrated sulfuric acid (18mol/L) with an equimolar ratio, and stirring at 70 ℃ to react for 8 hours. After the reaction is finished, water is evaporated under reduced pressure at 70 ℃ (the pressure is-0.09 MPa), and the ionic liquid catalyst N-methyl-3-sulfopropyl imidazole hydrogen sulfate is obtained.
Adding 67.6g of o-aminoacetophenone, 40g of chloroacetonitrile, 27ml of 1, 4-dioxane and 2g of N-methyl-3-sulfopropyl imidazole bisulfate prepared above into a 500ml reaction bottle, stirring for dissolving, reducing the temperature of a reaction system to 8 ℃, dropwise adding 90g of 30 wt% hydrochloric acid into the reaction system at a dropwise adding speed of 0.1ml/s, controlling the reaction temperature to be constant in the dropwise adding process, and continuing to react for 18h at 8 ℃ after the dropwise adding is finished to finish the reaction process.
After the reaction, 200ml of ammonia water (ammonia water concentration is 10 wt%) at 5 ℃ is added into the reaction system, and after stirring and crystallization at 5 ℃ for 30min, the mixture is filtered to obtain a filter cake, and after the filter cake is washed with water, the product 85.14g is obtained by recrystallization with 200ml of dichloromethane, the yield is 85.14%, and the HPLC purity is 99.6%.
Example 3
The synthesis method of the 2-chloromethyl-4-methyl quinazoline comprises the following specific operation methods:
preparing an ionic liquid catalyst N-methyl-3-sulfopropyl imidazole hexafluorophosphate: to a round bottom flask was added 50mL of ethyl acetate and 6.1g of 1, 3-propane sultone. In N2Magnetically stirring at 40 deg.C for 0.5h under protection, slowly adding 4.1g of N-methylimidazole dropwise via a constant pressure dropping funnel, and reacting at 80 deg.C for 3 h. After the reaction is finished, the temperature is reduced to room temperature, the mixture is filtered, a filter cake is washed by ethyl acetate, and the N-methyl-3-sulfopropyl imidazole inner salt (white solid) is obtained after vacuum drying. Adding the prepared inner salt into a round-bottom flask, adding 20ml of distilled water, stirring at room temperature to dissolve, slowly dropwise adding hexafluorophosphoric acid with an equal molar ratio, and stirring at 70 ℃ to react for 8 hours. After the reaction is finished, water is evaporated under reduced pressure at 70 ℃ (the pressure is-0.09 MPa), and the ionic liquid catalyst N-methyl-3-sulfopropyl imidazole hexafluorophosphate is obtained.
67.6g of o-aminoacetophenone, 40g of chloroacetonitrile, 33ml of 1, 4-dioxane and 2g of N-methyl-3-sulfopropylimidazole hexafluorophosphate prepared above are added into a 500ml reaction bottle, stirred and dissolved, the temperature of a reaction system is reduced to 10 ℃, 98g of 35 wt% hydrochloric acid is dropwise added into the reaction system, the dropwise adding speed is 0.1ml/s, the reaction temperature is controlled to be constant in the dropwise adding process, and after the dropwise adding is finished, the reaction is continued for 20 hours at 10 ℃ to finish the reaction process.
After the reaction, 200ml of ammonia water (ammonia concentration of 12 wt%) at 10 ℃ was added to the reaction system, and after stirring and crystallization at 10 ℃ for 30min, the mixture was filtered to obtain a filter cake, which was washed with water and recrystallized from 200ml of dichloromethane to obtain 84.50g of a product with a yield of 84.42% and a HPLC purity of 99.5%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (8)
1. A synthetic method of a linagliptin intermediate 2-chloromethyl-4-methyl quinazoline is characterized by comprising the following steps: synthesizing 2-chloromethyl-4-methyl quinazoline by taking o-aminoacetophenone and chloroacetonitrile as reaction raw materials, acidic ionic liquid as a catalyst and 1, 4-dioxane as a reaction solvent through a catalytic ring closure reaction under an acidic condition;
the acidic ionic liquid is one of N-methyl-3-sulfopropyl imidazole chloride salt, N-methyl-3-sulfopropyl imidazole bisulfate and N-methyl-3-sulfopropyl imidazole hexafluorophosphate;
the reaction temperature is 5-10 ℃;
and crystallizing after the reaction is finished, wherein the specific crystallization operation comprises the following steps: adding ammonia water with the temperature of 0-10 ℃ and the concentration of 8-12 wt% into the reaction system, keeping the temperature below 10 ℃, stirring for crystallization, filtering, dissolving the obtained filter cake in dichloromethane, and then recrystallizing.
2. The method for synthesizing linagliptin intermediate 2-chloromethyl-4-methyl quinazoline according to claim 1, characterized in that: the mol ratio of o-aminoacetophenone to chloroacetonitrile is 1: 1-1.2.
3. The method for synthesizing linagliptin intermediate 2-chloromethyl-4-methyl quinazoline according to claim 1, characterized in that: the addition amount of the acidic ionic liquid is 2.5-3.5% of the mass of the o-aminoacetophenone.
4. The method for synthesizing linagliptin intermediate 2-chloromethyl-4-methyl quinazoline according to claim 1, characterized in that: the adding amount of the 1, 4-dioxane is 40-50% of the mass of the o-amino acetophenone.
5. The method for synthesizing linagliptin intermediate 2-chloromethyl-4-methyl quinazoline according to claim 1, characterized in that: the acidic condition is maintained by dropping an inorganic acid solution into the reaction system.
6. The method for synthesizing linagliptin intermediate 2-chloromethyl-4-methyl quinazoline according to claim 5, characterized in that: the inorganic acid solution is 25-35 wt% hydrochloric acid solution, and the hydrochloric acid continuously reacts for 15-20h after the dripping is finished.
7. The method for synthesizing linagliptin intermediate 2-chloromethyl-4-methyl quinazoline according to claim 1, characterized in that: the adding amount of the ammonia water is 1.5 to 2.5 times of the volume of the reaction system.
8. The method for synthesizing linagliptin intermediate 2-chloromethyl-4-methyl quinazoline according to claim 1, characterized in that: the amount of dichloromethane is 2-3ml/g filter cake.
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Denomination of invention: Synthesis method of intermediate 2-chloromethyl-4-methylquinazoline for Liraglutine Effective date of registration: 20230913 Granted publication date: 20220222 Pledgee: Industrial and Commercial Bank of China Limited Cangzhou Bohai New Area Branch Pledgor: CANGZHOU SENARY CHEMICAL SCIENCE-TEC CO.,LTD. Registration number: Y2023980056576 |